Cardiac arrhythmias are disorders involving the electrical impulse generating system of the heart. The disorders include premature contractions (extrasystoles) originating in abnormal foci in atria or ventricles, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular fibrillation, and ventricular tachycardia. For further discussion, see, for example, C. S. Goodman and A. Gillman, eds. The Pharmacological Basis of Therapeutics; Sixth Edition, New York: Macmillan Publishing Co., 1980; pp. 761-767.
One means of treating cardiac arrhythmia is with the drug propafenone. Propafenone has been shown to be effective in suppressing both supraventricular and ventricular arrhythmias. (Michael A. Brodsky and Byron J. Allen. "Ventricular tachycardia in patients with impaired left ventricular function: the role of propafenone." Clin. Prog. in Electrophysical and Pacing, 4:546, 1986.) The antiarrhythmic action of propafenone appears to be due to its propensity to depress conduction and prolong the refractory period in myocardium. (Shen, et al., "Electrophysiologic and hemodynamic effects of intravenous propafenone in patients with recurrent ventricular tachycardia" JACC 3: 1291-1307, 1984)
Propafenone undergoes oxidative metabolism by hepatic microsomal enzymes. However, from person to person there are marked genetically determined differences in the rate of hepatic propafenone metabolism. About 10% of the U.S. Caucasian population are considered "poor metabolizers" and 90% are considered "extensive metabolizers." Variations between racial groups have also been reported in the distribution of poor and extensive metabolizers.
Extensive metabolizers of propafenone have lower blood levels and experience a shorter duration of effect than poor metabolizers. These extensive metabolizers may require more frequent dosages of higher amounts of propafenone to control their arrhythmia.
Consequently, current formulations of propafenone are metabolized too quickly by many individuals. Also, ideal blood levels may not be reached or may not be maintained for a long enough period of time to provide efficient control of cardiac arrhythmia.
The object of the present invention is to provide a formulation of propafenone and a means of administering this formulation which modulates propafenone oxidative metabolism. Other objectives are to decrease interindividual variations of propafenone metabolism; to uniformly raise blood levels among the total population taking propafenone; and to increase the duration of effect among these individuals. Achievement of these objectives would result in increased intervals between administration, improved medical management of patients with cardiac arrhythmia, and greater success in the treatment of this condition.